Compact Spiral-Wound Filter Elements, Modules And Systems

ABSTRACT

The present invention provides compact spiral-wound filter elements having cassette-like performance. The invention further provides filtration systems (e.g., TFF systems) and processes (e.g., SPTFF processes) employing compact spiral-wound filter elements having cassette-like performance.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/750,838, filed Jun. 25, 2015, which claims the benefit of U.S.Provisional Application No. 62/017,084, filed on Jun. 25, 2014. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND

Biopharmaceutical filtration systems often utilize cassette filters forthe ultrafiltration and diafiltration of macromolecules, such asmonoclonal antibodies. Cassette filters, such as high mass transferversions of Pellicon® 3 cassettes (EMD Millipore Corp., Billerica,Mass.), serve as the standard for desired system performance due totheir compactness, high mass transfer rate, low cross flow requirementsand acceptably low pressure drop. However, cassette filters must be runin compression holder assemblies, which typically consist of thickstainless steel holder plates and alignment rods. Compression is appliedto the filters by tightening nuts or energizing hydraulic pistons. Forsingle use applications, the cassettes are typically isolated from theexpensive housing assemblies to prevent the housing assemblies fromcoming into contact with process fluids. Such isolation is achievedthrough the use of liner plates or plastic jackets encapsulating thecassettes. Both the housing assemblies and liner plates/plastic jacketsare inconvenient to use and increase the cost and complexity offiltration systems.

Spiral-wound membrane modules are an attractive alternative to cassettefilters because they obviate the need for compression holder assemblies.However, conventional spiral-wound membrane elements have much lowerflux than cassette filters, and would require impractically large pumpsor long filtration flow paths to achieve similar flux as cassettefilters at the same cross flow rate, resulting in a system that isneither compact, nor easy to use. Accordingly, there is a need forefficient, compact, scalable and improved spiral-wound filter elementsand elements that provide the performance advantages of cassettefilters.

SUMMARY

The present invention is based, in part, on improved spiral-wound filterelements that provide the performance attributes of cassette filters.Accordingly, in one embodiment the present invention relates to aspiral-wound filter element having a permeate flux of at least about 70%of the mass transfer limited permeate flux of a reference cassettefilter operating at the same cross flow flux and a feed channel pressuredrop of no more than about 1.2 times the feed channel pressure drop ofthe reference cassette filter operating at the same cross flow flux. Inother embodiments, the permeate flux is at least about 80% or 90% of themass transfer limited permeate flux of the reference cassette filter. Infurther embodiments, a spiral-wound filter element has a feed channellength of about 6 inches (15.24 cm) to about 18 inches (45.72 cm). In aparticular embodiment, a spiral-wound filter element has a feed channellength of about 12.5 inches (31.75 cm) or less.

In another embodiment, the present invention relates to a TFF systemthat includes at least one spiral-wound filter element of the invention.In a particular embodiment, the TFF system can be operated in asingle-pass mode. In some embodiments, two or more spiral-wound filterelements that are fluidly connected in series or in parallel can beincluded in the TFF system. The TFF system can generally include a valveor flow meter that is positioned on a retentate outlet or conduitcarrying retentate from the system to a retentate container to controlan amount of retentate that is recirculated. The TFF system can alsoinclude a reservoir for diafiltration solution and a conduit fordelivering diafiltration to the feed reservoir.

In a further embodiment, the present invention relates to a process forfiltering a liquid feed that includes passing a liquid feed through atleast one spiral-wound filter element described of the invention,separating the liquid feed into permeate and retentate in the filterelement, and recovering the permeate and at least a portion of theretentate from the filter element. The process can be a tangential flowfiltration (TFF) process (e.g., a single-pass TFF (SPTFF) process). Incertain embodiments, the liquid feed can be passed through at least twospiral-wound filter elements of the invention that are fluidly connectedin the TFF system. A portion of the retentate, including about 10% orless of the retentante, can be recirculated through the at least one ofthe filter elements. The process can further include a diafiltrationstep, which includes concentration and dilution steps.

In another embodiment, the present invention relates to a method ofproducing a high turbulence-promoting feed screen that includes hot-rollcalendaring a woven fiber feed screen to a final height of about 350 μmby flattening or removing tangent points along an outer surface of thefeed screen.

The present invention provides improved spiral-wound filter elementsthat have several advantages. For example, the spiral-wound filterelements of the present invention can achieve permeate fluxes that areclose to or about the permeate fluxes provided by cassette filters whenoperating at the same cross-flow. Additionally, the spiral-wound filterelements of the present invention are able to achieve such permeatefluxes without the penalty of a greatly increased feed channel pressuredrop, which occurs in conventional spiral-wound filters. Thespiral-wound filter elements of the present invention also offer theperformance attributes of cassettes in a compact design that ensureseasy incorporation into filtration systems. Additionally, unlikecassettes, the spiral-wound filter elements of the present invention donot require compression housings or liners, and can be placed indisposable sleeves or liners providing increased ease-of use compared tocassettes, particularly for single-use systems. Accordingly, thespiral-wound filter elements of the present invention provide suitablealternatives to cassette filters for use in filtration systems andprocesses, including TFF systems and processes. FIG. 1 tabulates thecomparative properties of commercially available filtration devices,including a P3B030A01 cassette filter (EMD Millipore, Billerica, Mass.)and a variety of available spiral-wound filter elements, in relation tospiral-wound filter elements of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing will be apparent from the following more particulardescription of example embodiments, as illustrated in the accompanyingdrawings in which like reference characters refer to the same partsthroughout the different views. The drawings are not necessarily toscale, emphasis instead being placed upon illustrating embodiments.

FIG. 1 is a table listing comparative properties of commerciallyavailable filtration devices, including a cassette filter and a varietyof available spiral-wound filter elements, in relation to spiral-woundfilter elements of the present invention

FIG. 2 is a graph of permeate flux versus cross flow of a referencecassette filter and a comparative spiral-wound filter element.

FIG. 3 is an extrapolated graph of the graph of FIG. 2.

FIG. 4 is a schematic of spiral-wound filter elements in series.

FIG. 5 is a graph of pressure drop versus cross flow of a referencecassette filter (P3B030A01) and a comparative spiral-wound filterelement (Prep/Scale, CDUF006, 12″ length filter).

FIG. 6 is cross-sectional view of a spiral-wound filter element.

FIG. 7 is a cross-section view of bypass flow (annular) space around aconventional spiral-wound membrane element.

FIG. 8 is a schematic depicting a mechanism of ballooning.

FIG. 9 is a schematic depicting ballooning with a thick permeate screen(spacer).

FIG. 10 is a schematic depicting ballooning with a thin permeate screen.

FIG. 11 is a schematic depicting a comparison of bypass upon ballooningwith thick (left) and thin (right) permeate screens.

FIG. 12 is a schematic depicting imprinting of a feed screen into amembrane and mitigation of ballooning.

FIG. 13 is a schematic depicting an expanding feed screen and mitigationof ballooning.

FIG. 14 is a schematic depicting how feed flow permeates through onemembrane in outermost feed channel and permeates through two membranesin an inner feed channel.

FIG. 15 is a perspective view of a spiral-wound filter element.

FIG. 16 is a schematic of a membrane envelope of a spiral-wound filterelement.

FIG. 17 is a diagram of a Tangential Flow Filtration (TFF) system.

FIG. 18 is a graph showing the effect of different construction factorson the efficiency of spiral-wound filters.

FIG. 19 is a graph of cross flow ratio versus trans membrane pressure(TMP) required in a spiral-wound filter to obtain 36 lmh.

FIG. 20 is a graph of permeate flux versus cross flow for a conventionalcassette filter, a conventional prep/scale spiral-wound filter, andspiral-wound filter elements in accordance with embodiments of thepresent invention.

FIG. 21 is an image of an unaltered, non-calendared a-screen feedscreen.

FIG. 22 is an image of a modified a-screen feel screen that has beencalendared to remove tangents and reduce screen height.

FIG. 23 is a graph of permeate flux and pressure drop of embodiments ofthe present invention, including a 12″ spiral-wound filter element(formed from two 6″ spiral-wound filter elements and having a-screen forfeed spacer) and a 6″ spiral-wound filter element (having a calendareda-screen for a feed spacer).

FIG. 24 is a graph of permeate flux versus pressure drop of spiral-woundfilter elements in accordance with embodiments of the present invention,including a 12″ spiral-wound filter element (formed from two 6″spiral-wound filter elements having a-screens) and a 6″ spiral-woundfilter element (having a calendared a-screen for feed spacer each withBiomax membrane.

FIG. 25 is a graph of permeate flux versus cross flow of a series of two6″ spiral-wound filter sub-elements (forming a 12″ spiral-wound filterelement) in accordance with embodiments of the present invention andincluding PLCTK membrane and a-screen feed screens.

FIG. 26 is a graph of permeate flux versus cross flow of a series of two6″ spiral-wound filter sub-elements (forming a 12″ spiral-wound filterelement) in accordance with embodiments of the present invention andincluding PLCTK membrane and c-screen feed screens.

FIG. 27 is a graph of permeate flux versus cross flow of 12.5″spiral-wound filter elements with Biomax-30 membrane in accordance withembodiments of the present invention.

FIG. 28 is a graph of permeate flux versus cross flow of 12.5″spiral-wound filter elements with PLCTK (PLC30) membrane in accordancewith embodiments of the present invention.

FIG. 29 is a graph of permeate flux versus cross flow of a series of two6″ PLCTK membrane spiral-wound filter sub-elements (forming a 12″spiral-wound filter elements) before and after exposure to gammairradiation in accordance with embodiments of the present invention.

FIG. 30 is a graph of permeate flux versus cross flow of spiral-woundfilter elements including a 6″ PLCTK (nominal 30 kD membrane), and a 6″cross-linked Ultracel® 100 membrane (PLCHK), to produce a cross-linked30 kD membrane in accordance with embodiments of the present invention.

FIG. 31 is a graph of permeate flux versus cross-flow of single 12.5″long spiral-wound filter element with 0.22 m² or scaled down 0.11 m²sizes in accordance with embodiments of the present invention.

FIG. 32 is a graph of permeate flux versus cross-flow of spiral-woundfilter elements including PET feed screen in accordance with embodimentsof the present invention.

FIG. 33 is a graph of flux versus concentration of Bgg in a batchconcentration step using a TFF system having spiral-wound filterelements in accordance with embodiments of the present invention.

FIG. 34 is a graph of flux and pressure drop versus concentration of Bggin a batch concentration step using a TFF system having spiral-woundfilter elements in accordance with embodiments of the present invention.

FIG. 35 is a graph of fraction of salt remaining versus number ofdiafiltration volumes of spiral-wound filter elements in accordance withembodiments of the present invention.

FIG. 36 is a graph of fraction of salt remaining versus number ofdiafiltration volumes of scaled-down spiral-wound filter elements inaccordance with embodiments of the present invention.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains.

As used herein, the singular forms “a”, “an,” and “the” include pluralunless the context clearly dictates otherwise.

The expression “spiral-wound filter element” refers to a filtrationmembrane that is spirally wound about a core. A spiral-wound filterelement may be contained within a housing and may alternately bereferred to as a spiral-wound filter module.

“Cassette-like performance” or “cassette filter-like performance” meansperformance with a permeate flux of at least about 70% of the masstransfer limited permeate flux of a reference cassette filter and a feedchannel pressure drop of no more than about 1.2 times the feed channelpressure drop of a reference cassette filter operating at the samecross-flow flux.

“Pressure drop” refers to the drop in pressure (e.g., psid) within afeed channel over the length of the filter element.

“Flux” is the area-normalized flow rate.

“Permeate flux” is the area normalized flow rate of permeate in apermeate channel (e.g., Liters/hr/m2, lmh).

“Cross flow flux” is the area normalized average flow rate of retentatein a feed channel (e.g. Liters/min/m2, 1 mm).

“Mass transfer limited flux” is the maximum flux attainable regardlessof transmembrane pressure. It is proportional to the mass transfercoefficient, which is often described as the ratio of the solutediffusivity to the boundary layer thickness determined by hydrodynamicconditions in feed channel.

“Trans-membrane pressure drop” is the pressure drop normal to thesurface of a membrane.

“Cross flow” is the retentate flow rate between inlet and outlet of thefeed channel in a filter or a series of filters. Unless otherwisestated, “cross flow” refers to an average cross flow.

The terms “feed,” “feed sample” and “feed stream” refer to the solutionbeing introduced into a filtration module for separation.

The term “separation” generally refers to the act of separating the feedsample into two streams, a permeate stream and a retentate stream.

The terms “permeate” and “permeate stream” refer to that portion of thefeed that has permeated through the membrane.

The terms “diafiltrate”, “diafiltration buffer”, and “diafiltratestream” refer to the solution being used to wash permeate solutes out ofthe feed stream during a diafiltration process.

The terms “retentate” and “retentate stream” refer to the portion of thesolution that has been retained by the membrane, and the retentate isthe stream enriched in a retained species.

“Feed channel” refers to a conduit in a filtration assembly, module orelement for a feed.

“Permeate channel” refers to a conduit in a filtration assembly, module,or element for a permeate.

The expression “flow path” refers to a channel comprising a filtrationmembrane (e.g., ultrafiltration membrane, microfiltration membrane)through which the solution being filtered passes (e.g., in a tangentialflow mode). The flow path can have any topology which supportstangential flow (e.g., straight, coiled, arranged in zigzag fashion). Aflow path can be open, as in an example of channels formed by hollowfiber membranes, or have one or more flow obstructions, as in the case,for example, of rectangular channels formed by flat-sheet membranesspaced apart by woven or non-woven spacers.

“TFF assembly,” “TFF system” and “TFF apparatus” are usedinterchangeably herein to refer to a tangential flow filtration systemthat is configured for operation in a single-pass mode and/or arecirculation mode (e.g., full or partial recirculation).

“SPTFF assembly,” “SPTFF system” and “SPTFF apparatus” are usedinterchangeably herein to refer to a TFF system that is configured foroperation in a single-pass TFF mode.

“Single-pass mode” and “single pass TFF mode” refer to operatingconditions for a TFF system/assembly under which all or a portion of theretentate is not recirculated through the system.

“Single leaf” spirals are spiral-wound filter elements that can beformed with one continuous feed channel. They are generally made withone sheet of membrane.

“Multi-leaf” spirals are spiral-wound filter elements that have multiplefeed channels. They are generally made with more than 1 sheet ofmembrane; but can be made with 1 membrane sheet also.

A “cassette holder” refers to a compression assembly for one or morecassettes. Typically, when a cassette holder contains more than onecassette, the cassettes are configured for parallel processing,although, in some embodiments, the cassettes can be configured forserial processing.

A “cassette” refers to a cartridge or flat plate module comprisingfiltration (e.g., ultrafiltration or microfiltration) membrane sheet(s)suitable for TFF processes.

“Filtration membrane” refers to a selectively permeable membrane capableof use in a filtration system, such as a TFF system.

The terms “ultrafiltration membrane” and “UF membrane” are generallydefined as a membrane that has pore sizes in the range of between about1 nanometer to about 100 nanometers, or alternately defined by the“molecular weight cut off” of the membranes, expressed in units ofDaltons, and abbreviated as MWCO. In various embodiments, the presentinvention utilizes ultrafiltration membranes having MWCO ratings in therange from about 1,000 Daltons to a 1,000,000 Daltons.

The term “microfiltration membranes” and “MF membranes” are used hereinto refer to membranes that have pore sizes in the range between about0.1 micrometers to about 10 micrometers.

The term “high turbulence-promoting screen” as used herein refers to ascreen which increases cross flow velocity in a channel (e.g., a feedchannel) and promotes mixing near the membrane surface.

The term “expandable feed screen” or “expanding feed screen” means afeed screen that expands with ballooning of the feed channel to maintaincontact with a membrane face.

The term “plurality,” refers to two or more of a unit, element, ormodule.

“Fluidly connected” refers to a plurality of spiral-wound membrane TFFmodules that are connected to one another by one or more conduits for aliquid, such as, a feed channel, retentate channel and/or permeatechannel.

“Product” refers to a target compound that resides in the feed stream.Typically, a product will be a biomolecule (e.g., protein) of interest,such as a monoclonal antibody (mAb) residing in the feed stream.

“Processing” refers to the act of filtering (e.g., by TFF) a feedcontaining a product of interest and subsequently recovering the productin a concentrated and/or purified form. The concentrated product can berecovered from the filtration system (e.g., a TFF) assembly) in eitherthe retentate stream or permeate stream depending on the product's sizeand the pore size of the filtration membrane.

The expressions “parallel processing”, “processing in parallel”,“parallel operation” and “operation in parallel” refer to processing aproduct in a TFF assembly (e.g., SPTFF assembly) that contains aplurality of processing units that are fluidly connected by distributingthe feed directly from a feed channel or manifold to each of theprocessing units in the assembly.

The expressions “serial processing”, “processing in series”, “serialoperation” and “operation in series” refer to processing a product in aTFF assembly (e.g., SPTFF assembly) that contains a plurality ofprocessing units that are fluidly connected by distributing the feeddirectly from the feed channel to only the first processing unit in theassembly. In serial processing, each of the other, subsequent processingunits in the assembly receives its feed from the retentate line of thepreceding processing unit (e.g., the retentate from a first processingunit serves as the feed for a second, adjacent processing unit).

The expressions “conversion,” “single-pass conversion,” and “conversionper pass” are used herein to denote the fraction of the feed flow fluxthat permeates through the membrane in a single pass through the flowchannels, expressed as a percentage of the feed stream flow flux.

A description of example embodiments follows.

Comparison of Conventional Spiral-Wound Filter Elements to CassetteFilters

Conventional spiral-wound filter elements generally have much lower fluxthan cassette filters, rendering them inferior to cassette filters forseveral filtration applications. An example is shown in FIG. 2, in whichthe permeate flux of a benchmark cassette (P3B030A01C2JA48465-6945-.11m2) and a conventional spiral-wound filter element(Prep/Scale CDUF006TT-C1KA07028-09-.54m2) are plotted. For the exampleshown in FIG. 2, the mass transfer limited flux and pressure drop of theconventional spiral-wound filter element as a function of normalizedaverage cross flow rate was evaluated in a TFF system using 40 g/Lbovine gamma globulin (Bgg). The TFF system was run in total recyclemode. Retentate pressure was throttled to 15 psi to ensure that masstransfer limited flux was attained. FIG. 2 shows the permeate fluxversus crossflow in a conventional 6″ long cassette filter and aconventional 12.5″ long spiral-wound filter element. At a typical crossflow of 6 L/min-m2, the conventional spiral-wound filter element fluxwas about 2.7 times lower than the conventional cassette filter.

FIG. 3 shows an extrapolation of the results shown in FIG. 2. In orderto reach the desired 6 L/min·m² cassette filter flux, the conventionalspiral-wound filter module cross flow flux must increase about 4-fold,to 24 L/min·m².

Cross flow fluxes above 6 L/min·m² are less desirable for single use TFFsystems because they require larger pumps, which are not alwaysavailable, and larger piping, thereby resulting in a system having alarger footprint, higher capital costs, and larger hold-up volumes.Larger hold-up volumes reduce the maximum concentration factor and canreduce product recovery or lead to dilution of the final product pool.

Cross flow flux (e.g., L/min·m²) can be reduced by increasing the lengthof a feed channel flow path, which can be achieved by placing filterelements in series or by using filter elements having a longer feedchannel. Both methods can increase the membrane area for a given pumpingrate, while maintaining the approximate feed velocity, and hencepermeate flux, for typical low-conversion-per-pass applications (e.g.,about 10% of concentrated macromolecules). FIG. 4 illustrates thisprinciple. For example, to decrease cross flow flux 4-fold, the feedchannel path length must be increased 4-fold. However, this leads tovery long feed channel flow paths, often with more connections, andresults in a more complex system, which is undesirable.

Additionally, lengthening the feed channel flow path proportionallyincreases the pressure drop across the filter element. FIG. 5 shows thepressure drop as a function of cross flow for the reference cassette(P3B030A01 C2JA48465-6945-.11m2) and the conventional spiral-woundfilter element (Prep/Scale CDUF006TT-C1KA07028-09-.54m2) shown in FIGS.6 and 7. As discussed above, in order to meet the permeate flux of thecassette filter at 6 L/min·m², the spiral-wound filter element requiresa 4-fold higher cross flow rate. The pressure drop of spiral-woundfilter element at a 4-fold higher cross flow rate is about 24 psid. Whenthe feed path length of the spiral-wound filter element is increased4-fold (to reduce the cross flow 4-fold, down to the cassette filtertarget of 6 L/min·m²) the pressure drop increases proportionately. Thus,a 4-fold pressure drop gives a total feed channel path pressure drop of96 psid in the conventional spiral-wound filter element, which is 6.5times higher than the cassette filter.

Spiral-Wound Filter Elements Having Cassette-Like Performance

As described here, the present invention provides compact spiral-woundfilter elements that provide cassette-like performance. In oneembodiment, a spiral-wound filter element has a permeate flux of atleast about 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,100%, 105%, or 110%) of the mass transfer limited permeate flux of areference cassette filter operating at the same cross flow flux, and afeed channel pressure drop of no more than about 1.2 times (e.g., 1.2,1.1, 1.0, 0.8, or 0.5 times) the feed channel pressure drop of thereference cassette filter operating at the same cross flow flux. In aparticular embodiment, a spiral-wound filter element has a permeate fluxof at least about 80% of the mass transfer limited permeate flux of areference cassette filter operating at the same cross flow flux. Inanother embodiment, a spiral-wound filter element has a permeate flux ofat least about 90% of the mass transfer limited permeate flux of areference cassette filter operating at the same cross flow flux.

Typical operating conditions for spiral-wound filter elements of thepresent invention include cross flow fluxes in the range of about 0.1L/min·m² and about 12 L/min·m². Cross-flow fluxes in the range of 4 to 8L/min·m² are typical for recirculated batch filtration, while fluxes inthe range of 0.1 to 2 L/min·m² are typical for single-pass filtration.In a particular embodiment, an average operating cross flow flux isabout 6 L/min·m². Typical operating temperature can be in the range ofabout 15° C. to about 30° C., or more typically about 20° C. to about25° C. Typical retentate pressure can be in the range of about 10-20psig.

Cross flow flux can be determined by measuring an average feed flow ratein the TFF device (e.g., a spiral-wound filter element, or cassettefilter) and dividing the average by the membrane area in the TFF device.Average feed flow rate is the sum of feed and retentate flow divided bytwo. Average feed flow rate is often measured as the sum of theretentate flow rate and half the permeate flow rate. Cross flow flux istypically represented in units of liters per minute per square meter(L/min-m²). Flow rates can be measured with flow meters. Flow rates canbe measured by collecting a known volume (or weight, for a knowndensity) in a vessel over a known period of time.

Permeate flux can be determined by measuring the permeate flow rate inthe TFF device and dividing the flow rate by the membrane area in theTFF device. Permeate flow rate can be measured by collecting a knownvolume (or weight, for a known density) in a vessel (e.g. a graduatedcylinder) over a known period of time. Permeate flux is typicallyrepresented in units of liters per hour per square meter (e.g.,L/hr/m²).

Feed channel pressure drop can be determined by subtracting a measuredretentate pressure from a measured feed pressure, across the TFF device.Feed and retentate pressures can be measured with pressure gauges orpressure transducers.

The mass transfer limited flux of a TFF device at a given cross flowrate for a given feed solution is determined by increasing the observedtrans-membrane pressure until the permeate flux no longer increases.

A trans-membrane pressure drop can be determined by taking the averageof the feed and retentate pressure minus the permeate pressure.

In some embodiments, a spiral-wound filter element has an average crossflow flux of between about 2 and about 12 L/min·m², such as about 0.1and about 2 L/min·m². In further embodiments the spiral-wound filterelement can have a feed channel pressure drop of about 5 to about 30psid, such as about 5 to 20 psid.

Reference cassette filters can serve as a benchmark against whichperformance of a compact spiral-wound filter element of the presentinvention can be measured. Such cassettes may alternatively be referredto as benchmark cassette filters. Examples of suitable referencecassettes include, but are not limited to, various TFF cassettessupplied by EMD Millipore Corporation (Billerica, Mass.), such as, forexample, Pellicon® cassettes with Biomax® membrane or Ultracel®membrane. Particular examples of reference cassettes include Pellicon® 3mini-cassette, 0.11 m² made with a Biomax®-30 membrane, nominal 6″port-to-port feed path, an “a-screen” feed screen, and a “b-screen”permeate screen (P3B030A01); and, Pellicon® 3 mini-cassette, 0.11 m²made with an Ultracel®-30 membrane nominal 6″ port-to-port feed path, a“c-screen” feed screen, and a “b-screen” a permeate screen (P3C030C01).

Performance of spiral-wound filter elements of the present invention canbe evaluated against the performance of a reference cassette. Forexample, performance of the spiral-wound filter element at a cross flowof about 6 L/min·m² on 40 g/L Bgg at 23° C. can be at least 30 L/hr·m²permeate flux and no more than 14.5 psid feed channel pressure drop,with greater than 99% Bgg retention, for providing cassette-likeperformance.

Spiral-wound filter elements typically comprise, for example, a permeatedrainage tube (core), filtration membrane, feed spacer screen, permeatespacer screen, and adhesive (e.g., glue, epoxy). The permeate core canbe, for example, a polysulfone tube with a number of small holes locatedalong the expected width of the permeate envelope open end to allowdischarge of permeate from the filter element.

FIG. 6 shows a cross-sectional view of an example of a spiral-woundfilter element 100 in accordance with embodiments of the presentinvention. The spiral-wound filter element 100 includes membrane layers160, feed channel components 120 (e.g. feed spacer), and permeatechannel components 130 (e.g. permeate spacer) wound about a perforatedhollow core permeate collection tube 140. Arrows 150 indicate the flowdirection of permeate. The filter membrane layers 160 are in planarcontact with outer surfaces of the feed spacer 120. The feed spacer 120serves as both a mechanical stabilizer for channel geometry and aturbulence promoter for reducing polarization phenomena near themembrane surface. The permeate spacer 130 provides support for thefilter membrane layers 160 and maintains a flow channel for thedischarge of permeate.

Filtration membranes that can be used in the spiral-wound filterelements described herein are known in the art and include, for example,ultrafiltration membranes, microfiltration membranes, reverse-osmosismembranes, or nanofiltration membranes. Such membranes generally have anon-woven backing material or microporous membrane support. Filtrationmembranes can be formed, for example, from regenerated cellulose,polyarylsulphones, polyvinylidene fluoride (PVDF), polypropylene,polyester, polyethersulfone (PES), polyethylene, polyethersulfone,polysulfone, polyacrylonitrile, nylon, ethylene chlorotrifluoroethylene,polyimide, polyamide, fluoroethylenepropylene, perfluoroalkoxy,polytetrafluorethylene, polyetheretherketone, polysynidilenesulfide, andpolycarbonate. Particular examples of suitable filtration membranesinclude Biomax®-30 membranes and Ultracel®-30 membranes. Biomax®-30membranes are modified polyethersulfone membranes on non-wovenpolyolefin backings with nominal molecular weight cutoff of 30kilodaltons. Ultracel®-30 membranes are regenerated cellulose membraneson high density polyethylene 0.6 μm micro-porous substrates with nominalmolecular weight cutoff of 30 kilodaltons.

Feed spacers or screens are known in the art and can include a varietyof suitable materials (for example, polyethylene, polypropylene, andpolyester) and can have a variety of geometries (for example, extrudedbi-planar and woven monofilament mesh polypropylene, in square weave ortwill). Permeate spacers or screens are known in the art and aretypically similar to feed screens in materials and geometries, with theexception of Tricot double-knit polyester impregnated with epoxy.Particular examples of screens that can be used as feed spacers and/orpermeate spacers include, for example, a-screens, b-screens, andc-screens (Propyltex® screens, Sefar, QC, Canada). An a-screen is awoven 200 μm (approximate) mono-filament polypropylene diameter fiberscreen employing a square twill 2-over-1 right hand weave at 51 strandsper inch, having a total nominal weave thickness of 420 μm and open areaof about at 36%. A b-screen is a woven 150 μm (approximate)mono-filament polypropylene fiber screen employing a square twill2-over-1 right hand weave at 70 strands per inch and having totalnominal weave thickness of 320 μm and open area of ca at 34%. A c-screenis a woven 250 μm (approximate) mono-filament polypropylene diameterfiber screen employing a square twill 2-over-1 right hand weave at 42strands per inch and having total nominal weave thickness of 525 μm andopen area of ca at 34%.

Adhesives are known in the art and include. but are not limited to,glues, polyurethanes, or epoxies.

In some embodiments, spiral-wound filter elements of the presentinvention have short path lengths that are approximately the same asthose of cassette filters, which can be about 6″-18″ in length (e.g.,6″, 8″, 10″, 12″, 12.5″, 14″, 16″, and 18″). In a particular embodiment,a spiral-wound filter element has a feed channel length of about 12.5″(e.g., 12″, 12.5″, and 12.55″) or less. In another embodiment, aspiral-wound filter element has a feed channel length of about 6″ (e.g.,5.95″, 6″, 6.25″).

In some embodiments, a spiral-wound filter element can includesub-elements of shorter lengths in order to form a desired spiral-woundfilter element length. For example, a spiral-wound filter element havinga length of 12″ can be formed from two 6″ spiral-wound filtersub-elements.

As described herein, increasing feed channel efficiency can increase theperformance of spiral-wound membrane elements such that the spiral-woundfilter element can provide cassette-like performance. Embodiments of thepresent invention include spiral-wound filter elements having highturbulence-promoting feed screens. High turbulence-promoting screens canbe net-like woven mesh screens which increase cross flow velocity in thefeed channel of the spiral-wound filter element and promote mixing nearthe membrane. For example, a-screens and c-screens, described above, canbe high turbulence-promoting feed screens. High turbulence-promotingfeed screens are available commercially from Sefar, Inc. (Chicoutimi,Canada).

To increase efficiency while maintaining a short path length in aspiral-wound filter module, filter elements can be constructed usingthin feed screens and thin permeate screens. For example, a suitablefeed screen can have an uncompressed height (thickness) of about 600 μmor less (e.g., 600 μm, 550 μm, 500 μm, 450 μm, 400 μm, 300 μm, etc.). Ina particular embodiment, the feed screen has an uncompressed height ofabout 350 μm or less (e.g., 350 μm, 320 μm, 300 μm). A permeate screencan have an uncompressed height (thickness) of about 200 μm to about 800μm. In particular embodiments, the permeate screen has an uncompressedheight of about 600 μm or less (e.g., 600 μm, 560 μm, 610 μm). Incertain embodiments, the permeate screen has an uncompressed height ofabout 300 μm or less (e.g., 300 μm, 260 μm, 130 μm). In someembodiments, the feed channel length is less than about 800 times thefeed channel height.

The height of a permeate channel or feed channel will typically bedefined by a height of the screen (or “spacer”), if present, containedin the channel (e.g., in the absence of ballooning). In some instances,a screen (e.g., feed screen) can imprint into a membrane, for example,up to 65 μm on each side into an adjacent membrane. A compressed orimprinted screen (e.g., feed screen) can be desirable because it is ableto spring open or expand during operation to maintain contact withsurfaces of the adjacent membrane and limit ballooning. This can preventthe cross flow, or a portion of the cross flow, from bypassing the feedscreen.

Alternatively or in addition, thick and/or stiff feed permeate screens,which provide minimal compression during operation, can also be used toensure that high pressure feed does not cause permeate channels tocollapse. Permeate channels support discharge of permeate from thedevice and can further provide support to prevent a feed channel fromballooning. For example, with a compressed feed screen or a feed screenimprinted up to 65 μm on each side into an adjacent membrane, thesupporting permeate screen should compress less than 130 μm (forexample, approximately 50 psi at 23° C.) to limit ballooning of the feedchannel when the feed channel is energized with feed pressure and/orkeep the feed screen within the imprint during ballooning.

Stiff feed screens generally compress less than about 130 μm in heightunder compression of about 50 pounds per square inch at operatingtemperature (e.g., 23° C.). Thicker permeate screens generally requiregreater stiffness, e.g., in order to keep compression below a desiredlevel. Tensile modulus provides a measure of stiffness and is determinedby compressive pressure (force per area) times the screen thickness anddivided by the compression fraction (compression distance over originalthickness). For example, for a desired tensile modulus of 100 psi isdesirable for a compressive pressure of 50 psi on a 260 μm thick (thin)screen that compresses to 130 μm. Thicker screens, such as a 520 μmthick screen, require a higher tensile modulus of, for example, 200 psi,in order to keep compression below a desired level.

In another embodiment, the present invention relates to a method ofproducing a high turbulence-promoting feed screen that can beincorporated into a spiral-wound filter element. In some embodiments,the method is useful for producing a feed screen having a geometry thatmimics the feed channel geometry of cassette filters. The methodcomprises the steps of hot-roll calendaring a woven fiber feed screen toa final height of about 350 μm or less and flattening or removingtangent points along an outer surface of the feed screen. An example ofproducing a high-turbulence feed screen is provided in Example 3 herein.

Spiral-wound filter elements described herein have the advantage ofreducing or eliminating ballooning during filtration. As shown in FIG.7, spiral-wound filter elements can contain a bypass area between thespiral filter element and the housing. Ballooning, illustrated in FIG.8, occurs when high pressure in the feed channel pushes the membranesoutward under the positive transmembrane pressure (TMP) from the feedchannel to the permeate channel (used to drive the flow of permeatethrough the membrane) and can allow bypass flow around the feed screen.The use of a thicker and/or easily compressible permeate screen, asshown in FIG. 9, can result in increased ballooning during operation. Asshown in FIG. 10, the use of a thinner and/or stiffer permeate screencan result in decreased ballooning. Additionally, the use of a thinpermeate screen case can reduce the creation of a gap between feedspacer material and the membrane, as shown to the right in FIG. 11 andas compared to a thick permeate screen case shown to the left in FIG.11. FIGS. 12 and 13 illustrate additional approaches that reduce feedscreen bypass from ballooning, including a feed spacer that is imprintedinto the membrane and compression of feed spacer material duringproduction.

Accordingly, in some embodiments, the present invention providesspiral-wound filter elements having feed screens that are precompressed,expandable, and/or imprinted into the membrane.

In addition to decreasing ballooning, feed channel efficiency can beimproved by blocking an outermost feed channel of a spiral-wound filterelement. FIG. 14 illustrates the feed flow and permeate flow directionsfrom layers of membrane located within a housing. The outer feed flowchannels generally are underutilized since they only drive flux throughone membrane wall. Thus, in some embodiments, an outermost feed channellayer in the spiral-wound filter element is blocked (e.g. with glue,epoxy, etc.), such that feed is routed to the more efficient feedchannel(s) located closer to a core of the spiral-wound element.

By reducing ballooning effects and routing feed to more efficient feedchannels in spiral-wound filter elements, increased efficiencies can begained. With increased feed channel efficiency, spiral-wound filterelements having a short path length can be used in TFF systems, e.g.,SPTFF systems. Thus, in some embodiments of the present invention,efficiency and compactness are built into the design of the spiralelement. An estimate of efficiency can be provided by measuring thepressure drop needed to attain a target flux at a desired average crossflow flux.

Methods of assembling spiral-wound filter elements are known in the art.For example, a spiral-wound filter element can be assembled by lay-up ofa membrane (creating at least one membrane leaf from the folding of amembrane around a feed screen), attachment of the membrane leaf (orleaves) to a permeate core, and winding of the membrane leaf about thecore. FIG. 15 shows the assembly of a multi-leaf spiral-wound filterelement with arrows indicating feed flow direction and arrows indicatingpermeate flow within a membrane envelope 215. Additional layers ofpermeate spacer may be wound about the core (i.e., core wraps) beforethe membrane is introduced during winding (not shown in FIG. 15).Spiral-wound filter elements can be single-leaf (containing a singlemembrane envelope) or multi-leaf (containing two or more membraneenvelopes). As shown in FIG. 16, side and end seams are made to seal themembrane envelope so that feed cannot bypass the membrane to thepermeate channel. Permeate is directed to flow to the core of the filterelement.

In embodiments of the present invention, it may be desirable to reduceor eliminate membrane tails and/or screen tails during assembly ofspiral-wound filter elements. Methods of reducing or eliminatingmembrane and screen tails are known in the art and include, for example,providing an offset, trimming, or folding to reduce the amount of excessmembrane or screen that remains after the winding of the spiral-woundfilter element is completed. Reducing or eliminating membrane and screentails is referred to herein as “streamlining.”

Embodiments of the present invention include spiral-wound filterelements in a housing (e.g., reuseable housing, disposable housing),sleeve, or liner. Spiral-wound filter elements are placed in housings insuch a way as to enable connection to a filtration system (e.g. a TFFsystem), contain pressure, and keep feed, retentate, and permeatestreams separated. Housings can be stainless steel, plastic, or othersuitable material based on considerations such as strength, chemicalcompatibility, and safety of extractable materials for the intendedapplication. Several individual modules can be connected together in amanifold network. These manifolds provide parallel, series, or mixedflow of feed, retentate, and permeate through the module network.

Spiral-wound filter elements of the invention that are disposable orsingle use are particularly suitable for applications in thebiotechnology industry because single use avoids the need for cleaning,cleaning validation, and validation of the performance of the re-usedfilter. Furthermore, single-use spiral-wound filter elements and modulescompletely eliminate the possibility of cross-contamination, which is animportant aspect of pharmaceutical processing.

Tangential Flow Filtration Systems Comprising Spiral Wound FilterElements of the Invention

The spiral-wound filter elements of the present invention are suitablefor use in a variety of filtration systems and methods. In a particularembodiment a spiral-wound filter element is used in a TFF system. TFFsystems are known in the art. In a particular embodiment, the TFF systemcan be operated in a single pass mode (SPTFF). In another embodiment,the TFF system is operated in a recirculation mode. The TFF systems canhave one or more than one spiral-wound filter element described herein.In systems having more than one spiral-wound filter elements, thespiral-wound filter elements can be fluidly connected in series or inparallel, or both.

TFF systems generally provide a flow path and controls to deliver theconcentration and diafiltration processes sometimes required to convertfeed to a desired intermediate or final product and to recover theproduct at an acceptable concentration and purity. A TFF devicecontaining a spiral-wound filter module of the present invention, willgenerally include the necessary connections, separation capability, andmembrane area to accomplish the tangential flow filtration in therequired time.

An example TFF system is shown in FIG. 17. Pressurized feed from therecirculation tank is connected to the feed port of the spiral-woundfilter module or manifold (TFF device). Feed flows through the membranelined feed channel of the TFF device(s) under an applied trans-channelpressure drop, typically achieved by pressurizing the feed using a pump.Some of the solvent from the feed stream flows through the face of themembrane into the permeate channel and carries with it a portion of thepermeable species. The remaining concentrated feed stream flows out ofthe module or manifold through the retentate port. The permeate flowingfrom the module's permeate port is directed to a location that isdependent on the process, where it is either retained or discarded.

The TFF systems containing spiral-wound filter elements that areemployed in recirculating TFF methods can include at least one pump orcontrol valve for recirculating retentate through all or part of thesystem and at least one conduit for recirculating (e.g., carrying)retentate. The amount of retentate that is recirculated can becontrolled using, for example, a pump or a valve. A flow meter can beused to provide a process value for the pump or valve to control theamount of retentate that is recirculated. Thus, in some embodiments, theTFF systems described herein for use in the partial recirculation TFFmethods of the invention can further comprise a valve or pump and/or aflow meter for controlling recirculation of retentate. Preferably, thevalve or pump and/or flow meter is positioned on the retentate outlet orflow line carrying retentate out of the system to the retentatereceptacle.

Maximum achievable flux during TFF system operation is obtained byselection of an adequate transmembrane pressure (TMP) for permeatedischarge. This applies to pressure-dependent and mass-transfer-limitedregions of operation. For spiral-wound filters, attainment of thedesired TMP is determined by measurement at the end of the module. Forcassettes with two permeate outlets, attainment of the desired TMP isdetermined by the average feed channel pressure. The transmembranepressure must be sufficient to support both the pressure drop throughthe membrane and the maximum pressure to discharge permeate from thepermeate channel.

TFF Processes of the Invention

In one embodiment, the invention relates to a method of passing a liquidfeed through a spiral-wound filter element of the invention, separatingthe liquid feed into permeate and retentate in the filter element; andrecovering the permeate and at least a portion of the retentate from thefilter element.

The TFF systems described herein typically are also useful forsingle-pass TFF (SPTFF) methods and partial recirculation TFF methods.In a particular embodiment, the TFF process comprises recoveringpermeate and a portion of the retentate from the system in separatecontainers without recirculation through the TFF system, andrecirculating the remainder of the retentate through the TFF system atleast once.

Recirculating all or a portion of the retentate during start up providesa method by which to ensure that system has reached equilibrium and theretentate has achieved the desired concentration prior to collecting itinto the product vessel. It also provides a convenient way to respond tosystem upsets during processing to provide a more robust process. Thefraction of retentate that is recirculated can be adjusted viamodulation of the pump or control valve as a way to tune the system inorder to assure consistent retentate concentration and/or consistentretentate flow rate to the product collection vessel every run even iffeedstock protein concentration, new membrane permeability, membranefouling, membrane permeability, or membrane mass transfer or pressuredrop varies from batch to batch. This strategy has particular benefitsin the context of continuous processing where the success of subsequentoperations rely on the output of a previous operation. Recirculation ofretentate can improve cleaning effectiveness through increased crossflow velocity and reduce cleaning solution through recirculation.

Typically, at least about 50% of the retentate is collected after asingle pass, while the remainder of the retentate is recirculated.Preferably, about 10% or less (e.g., about 0.5%, about 1%, about 2%,about 5%, about 10%) of the retentate is recirculated after the firstpass through the TFF system.

The retentate that is being recirculated can be returned to any upstreamlocation in or before the TFF system. In one embodiment, the retentateis recirculated to the feed tank. In another embodiment, the retentateis recirculated to the feed line near the feed pump before the feedinlet on the TFF system.

In some embodiments, the methods described herein further compriseperforming diafiltration (e.g., to remove or lower the concentration ofsalts or solvents in the liquid feed, or to accomplish buffer exchange).In a preferred embodiment, the diafiltration is performed byconcentrating the liquid feed (e.g., by TFF) to reduce the diafiltrationvolume and then restoring the feed to its starting volume by addingdiafiltration solution (e.g., diafiltration buffer), a process which isknown in the art as discontinuous, or batch, diafiltration. In anotherembodiment, the diafiltration is performed by adding the diafiltratesolution to retentate to increase the diafiltration volume followed byconcentrating the sample to restore it to its original volume. In yetanother embodiment, the diafiltration is performed by adding thediafiltration solution to unfiltered feed at the same rate that permeateis removed from the TFF system, a process which is known in the art ascontinuous, or constant-volume, diafiltration. Suitable diafiltrationsolutions are well known and include, for example, water and variousaqueous buffer solutions. To perform diafiltration, the TFF system caninclude a reservoir or container for diafiltration solution and one ormore conduits for carrying diafiltration solution from the diafiltrationsolution container to the liquid feed tank.

To avoid extremes of concentration and in-line dilution as part of thediafiltration process (e.g. >90%), it is preferred to inject thediafiltrate into multiple sections of the filtration assembly to restorethe flow in the retentate section to the same flow as in the initialfeed. This requires matching the rate of diafiltrate buffer additionwith the rate of permeate removal. A preferred method is to use a singlepump with multiple pump heads containing the diafiltrate addition andpermeate removal flow lines (e.g. Peristaltic pump from Ismatec(Glattbrugg Switzerland)). Each pump head will have closely-matchedpumping rates so this process will be balanced and maintain efficientbuffer exchange. It is recommended to match flows for each of themultiple sections by using pumps containing up to 24 channels. Thediafiltrate can be injected into the retentate ports in manifolds orseparator plates.

The present invention provides improved spiral-wound filter elementsthat have several advantages. The spiral-wound filter elements of thepresent invention can achieve permeate fluxes that are close to or aboutthe permeate fluxes provided by cassette filters when operating at thesame cross-flow. Additionally, the spiral-wound filter elements of thepresent invention are able to achieve such permeate fluxes without thepenalty of a greatly increased feed channel pressure drop, which occursin conventional spiral-wound filters. The spiral-wound filter elementsof the present invention also offer the performance attributes ofcassettes in a compact design that ensures easy incorporation intofiltration systems. Additionally, unlike cassettes, the spiral-woundfilter elements of the present invention do not require compressionhousings or liners, and can be placed in disposable sleeves or linersproviding increased ease-of use compared to cassettes, particularly forsingle-pass systems. Accordingly, the spiral-wound filter elements ofthe present invention provide suitable alternatives to cassette filtersfor use in filtration systems and processes, including TFF systems andprocesses.

EXEMPLIFICATION

For the purposes of testing embodiments of the present invention,references are made to the following benchmark cassette filters:Pellicon® 3 mini-cassette, 0.11 m² made with a Biomax®-30 membrane,nominal 6″ port-to-port feed path, an “a-screen” feed screen, and a“b-screen” permeate screen (P3B030A01); and, a Pellicon® 3mini-cassette, 0.11 m² made with an Ultracel®-30 membrane nominal 6″port-to-port feed path, a “c-screen” feed screen, and a “b-screen” apermeate screen (P3C030C01).

In spiral-wound filter elements, prep/scale (P/S) screens were alsoutilized. For the purposes of testing embodiments of the presentinvention, references are made to the following P/S screens: a P/S feedscreen of high density polyethylene and employing a square plain1-over-1 weave at 33×33 strands per inch, having a nominal screenthickness of 508 μm and open area of ca at 42%; and, a P/S permeatescreen of biplanar polypropylene at 32.5×32.5 strands per inch, having anominal screen thickness of 508 μm and open area of about 39% asmeasured by scanning electron microscope (SEM).

A typical TFF test stand was used for examples described below. The TFFstand set was for a total recycle and included the following features: anominal 4 L sloped-to-drain-bottom tank with overhead impeller mixer;about 0.4 to 4 lpm Quattroflow diaphragm pump; mass flow meters forretentate and permeate streams; pressure gauges for feed, retentate andpermeate lines; diaphragm style retentate valve; and, temperaturecontrols through a concentric tube heat exchanger in the feed line and adouble-walled feed tank in a chiller-driven loop with a thermocouplethermometer in tank. Piping was 316L stainless steel with fractiontri-cover sanitary connectors and hose barb to flexible tubing whereneeded. TFF filter holders (EMD Millipore, Billerica, Mass.) includestainless steel Pellicon® Mini holder torqued to ca 190 in-lbs forPellicon® Mini cassettes and Prep/Scale holder for comparativespiral-wound filter module, Prep/Scale, and prototype spiral-woundfilter elements disposed in Prep/Scale housings.

Example 1: Examples of Compact Spiral-Wound Filter Elements HavingCassette-Like Performance

Five sample spiral-wound filter elements were prepared for cross-flow,energy, and pressure drop comparison. All samples were assembled withBiomax®-30 membranes and thin feed channels containing a-screens (highturbulence-promoting screens). Further, all samples had the annularspace between the spiral and the housing sleeve potted with 2-partcuring glue to prevent bypass flow around the spiral filter element andto block feed flow from entering the outer feed channel. Compact Spirals1 and 2 were prepared with a prep/scale (P/S) permeate screens. Spiral 2was additionally subjected to compression during the glue envelopecuring process by a series of hose clamps placed around thecircumference and along the length of the filter element (excluding theend-seam regions). Spirals 3, 4, and 5 were prepared with a Tricot (“T”)permeate screen, which is thinner than the P/S permeate screen ofSpirals 1 and 2. Samples 3 and 4 were prepared without compression.During the preparation of Samples 4 and 5, the feed screen and themembrane tail pieces extending beyond the permeate envelope end seamwere eliminated to eliminate flow in the feed screen tail. All sampleswere tested using a 0.22 μm filtered 40 g/L±2 g/L bovine gamma globulin(Bgg) solution of phosphate buffered saline. Operating conditions wereat 23° C.±1° C. and at a retentate pressure of 15 psig.

FIG. 18 shows the relative cross-flow, pressure drop, and energyrequired to achieve the same flux as the reference cassette (Pellicon® 3mini-cassette with Biomax®-30 membrane, P3B030A01). As may be seen froma comparison between Spirals 1 and 2 in FIG. 18, compression of thefilter element improves efficiency with little reduction in pressuredrop. Additional efficiency gains were obtained with the use of athinner permeate screen, even without compression, as may be seen inSpirals 3 and 4, where both pressure drop and energy consumption weredecreased. Efficiency of the thin permeate screen prototypes was furtherimproved by streamlining the device through the elimination of membraneand screen tails, as indicated with Spiral 4. Compression of astreamlined, thin permeate screen prototype did not gain any additionalefficiencies.

FIG. 19 shows the benefit of using a thinner permeate channel, either byspiral compression or by use of a thinner feed screen. As indicated inFIG. 19, a 2× reduction in ballooning flow was observed between Spiral 1(uncompressed P/S screen) and Spirals 3, 4, and 5.

Compact spirals described in Examples 2-12 were built with similarefficiency features to compact spiral 4 in FIG. 18, includingturbulence-promoting feed screens appropriate to the membranes, amembrane fold offset to minimize membrane tail (streamlined), pottedannulus, and tricot screens in the permeate channels.

Example 2: Series Operation of Two 6″ Compact Spiral-Wound FilterElements

In this experiment, 6″ long Biomax®-30 spiral prototypes of the presentinvention were tested to determine the flux and pressure drop as afunction of the average cross flow rate. Two 6″ spiral prototypesub-elements were placed in series to form each 12″ spiral-woundprototype element. For comparison, a reference cassette (Pellicon® 3mini-cassette with Biomax®-30 membrane, 0.11 m², P3B030A01) and aconventional spiral-wound filter (12.5″ Prep/Scale spiral filter, 0.54m², CDUF006TT) were also tested under the same conditions. All sampleswere tested using a 40 g/L±2 g/L bovine gamma globulin (Bgg) solution ofphosphate buffered saline at 23° C.

Cassette-like performance was achieved by connecting two of the 6″ longspiral prototypes in series. As shown in FIG. 20, the prototype compactspirals (Compact Spiral Series 1 and 2) achieved double the flux of thecomparative conventional spiral-wound filter and 80% of the fluxperformance of the reference cassette with a lower pressure drop.

Example 3: High-Turbulence-Promoting Feed Screen

In this experiment, a feed screen was made to mimic the feed channelgeometry expected under cassette-like compression in of the Pellicon® 3Biomax®-30 cassette filter with a high turbulence-promoting feed screen(a-screen). The channel height after cassette compression was estimatedas the feed screen height less two times the imprint depth of thea-screen into the Biomax®-30 membrane. A feed screen was created by hotroll calendaring an a-screen through heated wringers to melt down thetangents on the face of the screen and to create a feed screen with afinal height of about 340 μm. The original, non-calendared screen, whichhad a measured height of 397.6 μm, is shown in FIG. 21 (marked “length”in FIG. 21) and the final calendared a-screen, which had measuredheights of 331.1 and 343.0 μm in two locations, is shown in FIG. 22(marked “length” in FIG. 22).

The resulting performance of 6″ spiral-wound filters made with the thinfeed screen described above was similar to that obtained by 12″ longspirals (made from two 6″ spirals) having a conventional a-screen feedscreen, as shown in FIGS. 23 and 24.

Example 4: Two Compact Spiral-Wound Filter Elements in Series withUltracel®-30 Membrane

In this experiment, the development of a compact, efficient spiral-woundfilter element using an Ultracel® 30 membrane (as opposed to theBiomax®-30 membranes of the previous Examples) was evaluated. FIG. 25shows the results of a compact spiral incorporating an a-screen feedchannel spacer. It was found that the a-screen feed screen was tootight, resulting in good flux but an unacceptably high pressure drop.FIG. 26 shows the result of a compact spiral incorporating a c-screenfeed channel spacer, which is thicker and more open than an a-screenfeed channel spacer. The c-screen prototype generated an acceptable fluxand pressure drop, providing cassette-like performance.

Example 5: Operation of One 12.5″ Compact Spiral-Wound Filter Elementswith Biomax®-30 Membrane

In this experiment, a spiral-wound filter element made with the standardfeed screen for a Biomax®-30 membrane was made longer, to preclude theneed to run two 6″ spiral-wound filter elements in series in order toobtain cassette-like performance. A 12.5″ spiral-wound filter elementgives about twice the membrane area for a given diameter as comparedwith a 6″ spiral-wound filter element made with the same thin feedscreen. There are advantages to providing a larger membrane area in asingle spiral-wound filter element while maintaining the same diameter,for example, to reduce connections to scale up a TFF system in size andto reduce the number of parts.

The results are shown in FIG. 27. The 12.5″ compact spiral-woundprototypes achieved adequate flux and pressure drop, providingcassette-like performance, similar to the performance of a series of two6″ spirals.

Example 6: Operation of One 12.5″ Compact Spiral-Wound Filter Modulewith Ultracel®-30 Membrane

In this experiment, a spiral-wound filter elements made with a c-screenfeed spacers and Ultracel®-30 membranes (PLCTK) were made longer, topreclude the need to run two 6″ spiral-wound filter elements in seriesin order to obtain cassette-like performance. The results are shown inFIG. 28. As in the preceding example, the results indicate adequate fluxand pressure drop, providing cassette-like performance, similar to orslightly higher than the series of two 6″ spirals shown in Example 3.

Example 7: Gamma Irradiation for Sterilization Did not AffectPerformance of 6″ Long Compact Spiral-Wound Filter Modules withUltracel®-30 Membranes

In this experiment, prototype spiral capsules of this invention weretested for performance on Bgg solution, cleaned with 0.1N NaOH, flushed,subjected to 25 kGy gamma irradiation (a generally accepted low-endsterilization dose), and then tested on Bgg again. There is value inpre-sterilizing devices for single-use applications; for example, theydon't need to be sanitized before use, saving time, reducing cost, andreducing sanitizer waste. Since no preservative is required afterpre-sterilizing, less flus volume may be required. Gamma irradiation isthe current gold standard for sterilization procedures due to itsexcellent penetration through most samples. However, gamma irradiationcan affect the materials of construction, as well as the bioburdentarget species.

Performance of prototype modules before and after irradiation are shownin FIG. 29. Cassette-like performance was obtained in both samples. Theflux did not decrease and pressure drop was maintained in the samplesfollowing irradiation.

Example 8: Operation of 6″ Long Compact Spiral-Wound Filter Modules withIn-Situ Ultracel®-100 Membranes

Cross-linking solution was circulated at a target concentration andtemperature through a prototype spiral-wound filter module to convertUltracel®-100 membrane to Ultracel®-30 membrane. This procedure may beuseful to produce a potentially stronger version of Ultracel®-30membrane that is not available in roll stock.

Since only one 6″ cross-linked Ultracel®-100 spiral-wound filter elementwas available, it was compared with one 6″ Ultracel®-30 spiral-woundfilter element that was previously tested in series and that showedcassette-like performance. The results are shown in FIG. 30. Thecross-linked version of an Ultracel®-100 membrane performed almost thesame as the compact spiral with rollstock Ultracel®-30 membrane, withslightly lower retention.

Example 9: A Scaled Down Compact Spiral-Wound Filter Module

In this experiment, the length of spiral leaf (permeate envelope) wasshortened to make a scaled-down compact spiral-wound filter modulehaving less area for the same feed channel length, for comparison with astandard reference cassette size of 0.11 m², and to allowultrafiltration of smaller volumes of feed solution.

Ultracel®-30 TFF devices were evaluated, including the referencePellicon® 3 cassette (P3C030C01), the 0.22 m² and 0.11 m² 12.5″ longprototype spiral-wound filter modules. The results are shown in FIG. 31.The scaled-down prototype spiral-wound filter module, Compact Spiral 3(0.11 m²) had cassette-like performance, although mass transfer limitedflux was about 10% lower than that of the large area (0.22 m²)prototypes, Compact Spirals 1 and 2.

Example 10: 12.5″ Long Compact Spiral-Wound Filter Modules withUltracel®-30 Membrane and Alternate Material Feed Screen after Gamma andDimethylacetamide (DMAc) Exposure

The feed screen is an important factor in the level of extractables froma device subject to gamma irradiation due to the high wetted surfacearea. Low extractables are preferred for single-use TFF devices toreduce the amount of flushing required and to prevent contamination ofthe product pool. The baseline feed screen material used in the previousexamples (Examples 1-8) is polypropylene (PP), which is known to beattached by gamma irradiation.

In this experiment, a polyester (PET) feed screen, 07-350/34 (PETEX®screen from Sefar, QC, Canada) similar to the c-screen feed spacer wasused to preserve the high mass transfer coefficient while potentiallydecreasing gamma-related extractables.

The results are shown in FIG. 32. The PET feed screen prototypes(Compact Spirals 3 and 4) demonstrated cassette-like performance withsimilar Bgg retention as Compact Spirals 1 and 2 having PP feed screens.

Example 11: Batch Concentration of Bgg Solution Using a 30 kDRegenerated Cellulose 12.5″ Long Compact Spiral-Wound Filter Module

In this experiment bovine gamma globulin (Bgg) was concentrated from 4g/L to about 40 g/L, then concentrated from 40 g/L to about 200 g/L,using a retentate recycle tank. Permeate was sent to drain toconcentrate and sent back to the recycle tank to stabilize formeasurements and sample collection. Cross flow was held at 5 L/min·m²and retentate at 10 psi to mimic typical cassette system operation untilthe feed pressure reached a maximum of about 60 psi. Cross flow was thendecreased to 2.5 L/min·m² until feed pressure again reached 60 psi. Theretentate valve was then opened fully and concentration continued untilthe feed pressure again reached 60 psi.

FIG. 33 shows a very similar, but slightly lower, flux profile for thecompact spiral-wound prototypes of 0.11 m² and 0.23 m² sizes. Flux wasnoticeably lower for the longer permeate channel prototype (0.23 m²) dueto requiring 10 psi retentate. At lower fluxes, the bottleneckdisappears and the flux continues at the same level as the shorterpermeate channel prototype (0.11 m²). Raising retentate pressure to 15psi can be sufficient to maintain the flux of the 0.22 m² prototype atthe 0.11 m² level up to the highest flux shown in FIG. 34.

FIG. 34 shows a very similar pressure drop profile for the compactspiral-wound prototype (0.11 m²) and flux equivalent to the cassette,even at the highest pressures and pressure drops. While the compactspiral-wound prototype is not being compressed by a holder, it is stillable to maintain its feed channel geometry well enough at the highestpressures and pressure drops to match cassette flux.

Example 12: Diafiltration of Model Salt Water Solution with 12.5″Compact Spiral-Wound Membrane Module with Ultracel®-30 Membrane

In this experiment, the salt removal efficiency of a compactspiral-wound module was compared to a cassette using constant volumebatch diafiltration. One liter of 5 g/L sodium chloride solution wasloaded into the TFF system recirculation tank. Retentate was recycled tothe well-mixed recycle tank, while permeate was discharged to a separatecollection tank. Purified water was added to the recirculation tank at atarget rate equal to the permeate rate, thus maintaining an essentiallyconstant volume in the system.

The concentration in the tank was monitored with an Oakton conductivityprobe. Plotting the natural log of fraction salt remaining versus thenumber of diafiltration volumes permeated yields a line having a slopethat is the negative of the sieving coefficient (i.e., ln(C/Co)=−SN).Plotting fraction salt remaining on a log scale allows an easyassessment of the “log reduction value” of the salt, where 1 logreduction is 10 fold, 2 log reductions is 100 fold, and so forth. FIGS.35 and 36 show that the compact spirals (Compact Spiral 1 and CompactSpiral 2) gave similar salt reduction rate as the benchmark Pellicon® 3cassette. This applied to both of the compact spiral prototype designstested, including the 0.11 m² (short permeate channel, Compact Spiral 2)and the 0.24 m² (long permeate channel, Compact Spiral 1) prototypes.

The relevant teachings of all patents, published applications andreferences cited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A method of producing a feed screen, comprisinghot-roll calendaring a woven fiber screen to a final height of 600 μm orless and flattening or removing tangent points along an outer surface ofthe screen.
 2. The method of claim 1, wherein the final height is of 350μm or less.
 3. A feed spacer comprising a woven fiber screen having aheight of 600 μm or less and flattened or removed tangent points alongan outer surface of the feed screen.
 4. The feed spacer of claim 3,wherein the woven fiber screen has a height of 350 μm or less.
 5. Thefeed spacer of claim 3, wherein the woven fiber screen is compressible.6. A spiral-wound filter element comprising a feed spacer of claim
 3. 7.The spiral-wound filter element of claim 6, further comprising: apermeate screen having a height of 300 μm or less; and a filtrationmembrane.
 8. The spiral-wound filter element of claim 7, wherein thefeed spacer is imprinted into the filtration membrane.
 9. Thespiral-wound filter element of claim 8, wherein at least one surface ofthe feed spacer is imprinted up to 65 μm into the filtration membrane.10. The spiral-wound filter element of claim 7, wherein the feed spaceris configured to expand to maintain contact with a surface of thefiltration membrane during operation.
 11. The spiral-wound element ofclaim 7, further comprising a housing, wherein an annular space betweenthe filtration membrane and the housing is blocked.
 12. The spiral-woundfilter element of claim 7, wherein the filtration membrane is amicrofiltration membrane or an ultrafiltration membrane.
 13. Atangential flow filtration (TFF) system comprising at least one filterelement of claim 6.